Tet1 activity and function in helper T cells

辅助 T 细胞中的 Tet1 活性和功能

• 批准号: 8897261
• 负责人: Amy Susan Weinmann
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897261
• 关键词: Address; Area; BTB/POZ Domain; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Complex; Cytosine; DNA; DNA Methylation; DNA Modification Process; DNA Packaging; DNA Sequence Alteration; DNA biosynthesis; Data; Development; Disease; Enzymes; Epigenetic Process; Event; Excision; Future; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genome; Genomic Segment; Genomics; Goals; Health; Helper-Inducer T-Lymphocyte; Hematopoietic Neoplasms; High Prevalence; Immune; Immune response; Immune system; Influenza; Interleukin-2; Knowledge; Malignant Neoplasms; Mammalian Cell; Mediating; Memory; Methylation; Modification; Molecular Profiling; Mutation; Nucleic Acid Regulatory Sequences; Organism; Pattern; Phenotype; Play; Ploidies; Population; Process; Protein Family; Protein translocation; Proteins; Recruitment Activity; Repression; Research; Research Priority; Role; Site; Specific qualifier value; Specificity; Structure of germinal center of lymph node; T cell differentiation; T cell response; T memory cell; T-Cell Development; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Tissue-Specific Gene Expression; Virus Diseases; base; cell type; cellular development; demethylation; epigenetic profiling; flexibility; histone methylation; histone modification; human disease; insight; leukemia/lymphoma; methylation pattern; novel; programs; promoter; research study; response; transcription factor; vaccination strategy

DESCRIPTION (provided by applicant): The importance of properly establishing and maintaining epigenetic states in cellular development is unmistakable. The critical role for this process is highlighted by the number of mutations in epigenetic modifying proteins that are associated with human diseases, with a particularly high prevalence found in cancers. Similarly in the immune system, the precise coordination of epigenetic events is also required for cellular differentiation, and blood cancers such as leukemia and lymphoma often have mutations that impact the functions of epigenetic-modifying complexes. Recent research efforts have focused on profiling epigenetic modifications to define their cell-type and activation-state specific distribution. There also has been an emphasis on correlating changes in epigenetic patterns with human disease states. However, a major gap in our current knowledge has been defining the events that control the site specific targeting of the enzymatic machinery that regulates epigenetic patterns in unique cellular states. This is a high impact area of research because cell-type and activation-state specific epigenetic patterns cannot be explained without knowledge of the mechanisms that direct epigenetic-modifying complexes to unique sites in different cellular contexts. The focus of this proposal will be on the site-specific genomic targeting and functional activity of the DNA- demethylase Tet1 in helper T cells. Until recently, i was unclear if a cell possessed enzymatic machinery with the potential to actively remove the methyl modification on cytosine bases within the DNA. Some of the first hints that active DNA demethylation occurs in mammalian cells came from studies in T cells examining the IL-2 promoter, where the DNA replication-independent removal of cytosine methylation modifications was experimentally observed. The discovery of the ten-eleven-translocation (TET) protein family provided the first evidence that cytosine methylation could be broken down by a cellular enzyme into a hydroxymethylated state, with the potential to then be successively converted to the unmethylated state. Notably, mutations in TET proteins are found in a number of blood cancers, highlighting the importance of this protein family in immune cell development. In this proposal, we will for the first time define the mechanisms that target Tet1 to specific genomic loci in helpe T cells and its importance in the immune response. These studies will form the basis for understanding the site-specific targeting of Tet1 to loci in helper T cell development and how this impacts cellular transitions as well as the functional potential of the cells during an immune response to viral infection.

描述（由申请人提供）：在细胞发育中正确建立和维持表观遗传状态的重要性是不容置疑的。与人类疾病相关的表观遗传修饰蛋白的突变数量突出了这一过程的关键作用，在癌症中发现的发病率特别高。类似地，在免疫系统中，细胞分化也需要表观遗传事件的精确协调，而白血病和淋巴瘤等血癌通常具有影响表观遗传修饰复合物功能的突变。最近的研究工作集中在分析表观遗传修饰，以确定其细胞类型和激活状态的特异性分布。人们还强调表观遗传模式的变化与人类疾病状态的相关性。然而，在我们目前的知识中，一个主要的空白一直是定义控制在独特细胞状态下调节表观遗传模式的酶机制的位点特异性靶向的事件。这是一个影响很大的研究领域，因为如果不了解将表观遗传修饰复合物引导到不同细胞环境中独特位置的机制，就无法解释细胞类型和激活状态特定的表观遗传模式。本研究的重点是辅助性T细胞中DNA去甲基化酶Tet1的位点特异性基因组靶向和功能活性。直到最近，人们还不清楚细胞是否具有主动去除DNA内胞嘧啶碱基甲基修饰的酶机制。哺乳动物细胞中主动DNA去甲基化发生的一些最初迹象来自于对T细胞检查IL-2启动子的研究，在实验中观察到DNA复制独立的胞嘧啶甲基化修饰去除。10 - 11易位（TET）蛋白家族的发现提供了第一个证据，证明胞嘧啶甲基化可以被细胞酶分解成羟甲基化状态，然后有可能依次转化为非甲基化状态。值得注意的是，在许多血癌中发现TET蛋白突变，突出了该蛋白家族在免疫细胞发育中的重要性。在这项提议中，我们将首次确定Tet1靶向特异性T细胞基因组位点的机制及其在免疫应答中的重要性。这些研究将为理解辅助性T细胞发育中Tet1位点特异性靶向以及它如何影响细胞转变以及免疫过程中细胞的功能潜力奠定基础